ES2745506T3 - Anti-tumor combination comprising cabazitaxel and cisplatin - Google Patents

Abstract

Combination comprising cabazitaxel, which may be in the form of an anhydrous base, a hydrate or a solvate, and cisplatin, said combination being for administration of cabazitaxel by infusion at a dose of 15 to 25 mg / m2 and for the administration of cisplatin by infusion at a dose of 75 mg / m2, for use in the treatment of cancer.

Description

DESCRIPTION

Anti-tumor combination comprising cabazitaxel and cisplatin

The present invention relates to an anti-tumor combination comprising cabazitaxel, which may be in the form of an anhydrous base, a hydrate or a solvate, and cisplatin. The present invention further relates to a pharmaceutical composition containing this combination and to the use of this combination and / or pharmaceutical composition in the treatment of neoplastic diseases, more particularly in the treatment of cancer. [State of the art]

WO96 / 30355 discloses taxoid derivatives, including cabazitaxel, useful as antitumor agents. This document also discloses a long list of other drugs that can be used as co-treatment with these taxoids. In this list, platinum complexes such as cisplatin are cited. No data supporting this treatment is disclosed in this document.

WO2010 / 128258 discloses an antitumor combination comprising cabazitaxel and capecitabine in the treatment of metastatic breast cancer for patients who progress after previous treatment with anthracyclines and taxanes.

A phase I study (NCT00925743) is currently underway to evaluate the effects of combining cabazitaxel with cisplatin given every 3 weeks in patients with advanced solid cancer. The disclosure published on the clinicaltrials.gov site does not yield results for this study.

Some documents present the combination of different taxane compounds with platinum compounds in different types of cancer. Crown et al. (Lancet 2000; 355: 1176-78) describes the use of taxanes as anticancer cytotoxic, and more particularly combinations between paclitaxel and cisplatin or docetaxel and doxorubicin. Crown et al. (Breast Cancer Research and Treatment 79 (Suppl. 1): S11-S18, 2003) discloses combinations between docetaxel and trastuzumab or triple docetaxel-platinum-trastuzumab therapy including cisplatin or carboplatin, in the treatment of metastatic breast cancer. Mc Guire (Journal of Clinical Oncology, Vol 21, No. 10s (Supplement May 15), 2003: pp 133s-135s) discloses combinations between paclitaxel and cisplatin or carboplatin in ovarian cancer. Rigas (The Oncologist, Vol 9, Suppl 2, 2004, pp 16-23) describes combinations between docetaxel or paclitaxel with cisplatin or carboplatin for patients with non-small cell lung cancer.

[Technical problem]

There is always a need to find new antitumor treatments.

The invention addresses that need by providing an antitumor combination comprising cabazitaxel, which may be in the form of anhydrous base, a hydrate or a solvate, and cisplatin.

In fact, it has now been shown that the efficacy of cabazitaxel can be greatly improved when administered in combination with cisplatin. Furthermore, it has now been shown that the combination according to the invention is well tolerated, does not exacerbate the toxicity of each of the antitumor agents and allows the treatment of tumors either by stabilization or by induction of partial or complete regression. of the tumor.

[Brief description of the invention]

The present invention relates to an antitumor combination comprising cabazitaxel, which may be in the form of an anhydrous base, a hydrate or a solvate, and cisplatin.

The combination according to the invention is well tolerated, does not exacerbate the toxicity of each of the antitumor agents and allows the treatment of tumors either by stabilization or by inducing partial or complete regression of the tumor.

The present invention further relates to a pharmaceutical composition containing this combination.

The present invention further relates to a pharmaceutical kit comprising:

(i) a first galenic formulation comprising cabazitaxel in the form of a free base or of an addition salt with a pharmaceutically acceptable acid, or in the form of a hydrate or a solvate;

(ii) a second galenic formulation comprising cisplatin;

both galenic formulations (i) and (ii) being intended to be administered independently, each administration being simultaneous, separate or extended with respect to the other.

The present invention further relates to the use of this combination and / or pharmaceutical composition and / or pharmaceutical kit in the treatment of neoplastic diseases, more particularly in the treatment of cancer. [Definitions]

Cabazitaxel is an antitumor agent of the taxoid family and has the following formula:

It can be in the form of an anhydrous base, a hydrate or a solvate.

The chemical name of cabazitaxel is (2R, 3S) -3-ferc-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of 4a-acetoxy-2a-benzoyloxy-5p, 20-epoxy-1p-hydroxy-7p, 10p-dimethoxy- 9-oxo-11-taxen-13a-yl. Cabazitaxel is synonymously known as (2a, 5p, 7p, 10p, 13a) -4-acetoxy-13 - ({(2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-3 benzoate. -phenylpropanolyl} oxy) -1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxitax-11-en-2-yl.

This compound and one of its preparative methods is described in WO96 / 30355, EP0817779B1 and US5847170.

Cabazitaxel can be administered in the form of a base (cf. the formula above), or in the form of a hydrate. It can also be a solvate, that is to say a molecular complex characterized by the incorporation of the crystallization solvent into the crystal of the molecule of the active principle (see in this regard page 1276 of J. Pharm. Sci.

1975, 64 (8), 1269-1288).

In particular, it can be an acetone solvate, and, more particularly, it can be the solvate described in WO2005 / 02846. It can be a cabazitaxel acetone solvate containing between 5% and 8% and preferably between 5% and 7% by weight of acetone (% means acetone content / acetone content + cabazitaxel x 100). An average acetone content value is 7%, which roughly represents the stoichiometry of acetone, which is 6.5% for a solvate containing one molecule of acetone. The procedure described below allows the preparation of a cabazitaxel acetonic solvate: 940 ml of purified water at 20 ± 5 ° C (room temperature) are added to a solution of 207 g of (2R, 3S) -3-ferc-butoxycarbonylamino- 4a-Acetoxy-2a-benzoyloxy-5p, 20-epoxy-1p-hydroxy-7p, 10p-dimethoxy-9-oxo-11-taxen-13a-yl 2-hydroxy-3-phenylpropionate at approximately 92 wt% approximately 2 liters of acetone, followed by seeding with a suspension of 2 g of (2R, 3S) -3-fercbutoxycarbonylamino-2-hydroxy-3-phenylpropionate of 4a-acetoxy-2a-benzoyloxy-5p, 20-epoxy-1 p-hydroxy-7p, 10p-dimethoxy-9-oxo-11-taxen-13a-yl isolated from acetone / water in a mixture of 20 ml of water and 20 ml of acetone. The resulting mixture is stirred for approximately 10 to 22 hours, and 1.5 liters of purified water are added over 4 to 5 hours. This mixture is stirred for 60 to 90 minutes, and then the suspension is filtered under reduced pressure. The cake is washed on the filter with a solution prepared from 450 ml of acetone and 550 ml of purified water, and then heated in an oven at 55 ° C under reduced pressure (0.7 kPa) for 4 hours. 197 g of 4a-acetoxy-2a-benzoyloxy-5p, 20-epoxy-1p-hydroxy-7p, 10p-dimethoxy-9 are obtained (2R, 3S) -3-ferc-butoxycarbonylamino-2-hydroxy-3-phenylpropionate -oxo-11-taxen-13a-yl-acetone containing 0.1% water and 7.2% acetone (theoretical amount: 6.5% for a stoichiometric solvate).

Cabazitaxel is administered parenterally, through intravenous administration. A galenic form of cabazitaxel suitable for intravenous infusion administration is one in which cabazitaxel is dissolves in water in the presence of excipients chosen from surfactants, cosolvents, glucose or sodium chloride, etc. For example, a galenic form of cabazitaxel can be prepared by diluting a cabazitaxel premix solution contained in a sterile vial (80 mg cabazitaxel 2 ml polysorbate 80 solvent) with a sterile vial containing a 6 ml solution of water and ethanol (13% by weight 95% ethanol) to obtain 8 ml of a solution ready to be rediluted in an infusion bag. The concentration of cabazitaxel in this ready-to-dilute solution is approximately 10 mg / ml. The infusion is then prepared by injecting the appropriate amount of this ready-to-redilute solution into the infusion bag containing water and glucose (approximately 5%) or sodium chloride (approximately 0.9%).

Cisplatin is a platinum derivative used to treat various types of cancers, including sarcomas, some carcinomas (eg small cell lung and ovarian cancer), lymphomas, and germ cell tumors. It was the first member of a class of anticancer drugs that also includes carboplatin and oxaliplatin. These platinum complexes react in vivo, binding to and causing DNA crosslinking, which ultimately triggers apoptosis (programmed cell death).

Effective amount: The amount of a pharmaceutical compound that has an effect on the treated tumor.

Pharmaceutically Acceptable Acid: organic or inorganic acid having low toxicity (see "Pharmaceutical salts" J.Pharm.Sci. 1977, 66, 1-19);

Therapeutic synergy

The improved efficacy of the combination according to the invention can be demonstrated by determining the therapeutic synergy.

A combination manifests therapeutic synergy if it is therapeutically superior to the best study agent used only at its maximum tolerated dose (HNTD or highest non-toxic dose) or at its highest proven dose when toxicity cannot be achieved in the animal species.

This efficiency can be quantified, for example, by log10 cell destruction, which is determined according to the following formula:

log10 cell destruction = T-C (days) / 3.32xTd

where T-C represents tumor growth retardation, which is the median time in days for tumors in the treated group (T) and tumors in the control group (C) to have reached a predetermined value (1 g for example ), and Td represents the time in days necessary for the tumor volume to double in control animals [TH Corbett et al., Cancer, 40: 2660-2680 (1977); FM Schabel et al., Cancer Drug Development, Part B, Methods in Cancer Research, 17: 3-51, New York, Academic Press Inc. (1979)].

A product is considered to be active if log10 cell destruction is greater than or equal to 0.7. A product is considered to be very active if log10 cell destruction is greater than or equal to 2.8.

The combination will manifest therapeutic synergy when the log10 cell kill is greater than the log10 cell kill value of the best constituent administered alone at its maximum tolerated dose (at least 1 log cell kill).

The efficacy of the combinations on solid tumors can be determined experimentally as follows: The animals submitted to the experiment, generally mice, are bilaterally grafted subcutaneously with 30 to 60 mg of a tumor fragment on day 0. The animals are implanted with a murine tumor grafted into the syngeneic strain of mice of tumor origin, or by means of a rodent or human tumor xenografted in immunocompromised mice. A few days after tumor implantation, the mice are randomized according to their body weight to the different treatment and control groups. Animals are observed every day. The different groups of animals are weighed daily during the treatment until the maximum weight loss is reached and the subsequent total weight recovery has occurred. The groups are then weighed once or twice a week until the end of the test.

Tumors are measured 1 to 5 times per week, depending on the tumor's doubling time, until the tumor reaches approximately 2 g, or until the animal dies (if this occurs before the tumor reaches 2 g). Animals underwent autopsy immediately after euthanasia or death. The antitumor activity is determined according to the different parameters registered.

[Description of the invention]

The present invention relates to an antitumor combination comprising cabazitaxel, which may be in the form of an anhydrous base, a hydrate or a solvate, and cisplatin.

For example, cabazitaxel may be in the form of an acetone solvate, and more particularly it may be the solvate described in WO2005 / 02846.

Cabazitaxel acetone solvate may contain between 5% and 8% and preferably between 5% and 7% by weight of acetone (% means acetone content / acetone content + cabazitaxel x 100). An average acetone content value is 7%, which roughly represents the stoichiometry of acetone, which is 6.5% for a solvate containing one molecule of acetone.

The present invention also relates to an antitumor combination comprising an effective amount of cabazitaxel and an effective amount of cisplatin.

The present invention also relates to an antitumor combination showing therapeutic synergy.

The combination according to the invention is well tolerated, does not exacerbate the toxicity of each of the antitumor agents and allows the treatment of tumors either by stabilization or by inducing partial or complete regression of the tumor.

Cabazitaxel is administered by infusion (intravenous infusion) at a dose of 15 to 25 mg / m2, for example chosen from the following doses: 15; 20 and 25 mg / m2.

Cisplatin can be administered by infusion (intravenous infusion) at a dose of 75 mg / m2.

Thus, the invention also relates to a combination comprising cabazitaxel and cisplatin, cabazitaxel being in the form of a free base or of an addition salt with a pharmaceutically acceptable acid, or in the form of a hydrate or a solvate, the combination for administration of cabazitaxel by infusion at a dose of 15 to 25 mg / m2.

Thus, the invention also relates to a combination comprising cabazitaxel and cisplatin, cabazitaxel being in the form of a free base or of an addition salt with a pharmaceutically acceptable acid, or in the form of a hydrate or a solvate, the combination for administration of cisplatin by infusion at a dose of 75 mg / m2.

Thus, the invention also relates to a combination comprising cabazitaxel and cisplatin, cabazitaxel being in the form of a free base or of an addition salt with a pharmaceutically acceptable acid, or in the form of a hydrate or a solvate, the combination for administration of cabazitaxel by infusion at a dose of 15 mg / m2 and for administration of cisplatin by infusion at a dose of 75 mg / m2.

The cycle of administration of the two antitumor agents is repeated with an interval between two administrations of cabazitaxel of three weeks.

The use of cabazitaxel and cisplatin for the preparation of a combination according to the invention is also part of the invention.

The present invention further relates to the combination according to the present invention for use as a medicament in the treatment of neoplastic diseases, more particularly in the treatment of cancer. The present invention further relates to the pharmaceutical composition according to the present invention for use as a medicament in the treatment of neoplastic diseases, more particularly in the treatment of cancer.

Cabazitaxel and cisplatin can be administered simultaneously, semi-simultaneously, separately, or spaced over a period in order to obtain the maximum efficacy of the combination; Each administration may vary in duration from rapid administration to continuous infusion.

As a result, for the purposes of the present invention, the combination is not limited exclusively to that obtained by physical association of the constituents, but also to those that allow separate administration, which may be simultaneous or spaced along a time frame.

In the combinations according to the invention, the application of whose constituents can be simultaneous, separated or spaced over a period of time, it is especially advantageous that the amount of cabazitaxel represents from 10 to 90% by weight of the combination, being possible that this content varies according to the nature of the associated substance, the efficacy sought and the nature of the cancer to be treated.

In the combination according to the invention, cabazitaxel and cisplatin are preferably administered parenterally, for example intravenously.

The invention also relates to a pharmaceutical kit comprising:

(iii) a first galenic formulation comprising cabazitaxel in the form of a free base or of an addition salt with a pharmaceutically acceptable acid, or in the form of a hydrate of a solvate;

(iv) a second galenic formulation comprising cisplatin;

both galenic formulations (i) and (ii) being intended to be administered independently, each administration being simultaneous, separate or extended with respect to the other.

The invention also relates to the above pharmaceutical kit for use in the treatment of neoplastic diseases, more particularly in the treatment of cancers.

The invention also relates to the above pharmaceutical kit adapted for administration of cabazitaxel by infusion at a dose of 15 mg / m2 and for administration of cisplatin by infusion at a dose of 75 mg / m2. The invention also relates to the above pharmaceutical kit where the cycle of administration of the two antitumor agents is repeated with an interval between two administrations of cabazitaxel of three weeks. In another aspect, the invention provides an article of manufacture comprising:

a packaging material; the above disclosed pharmaceutical combination comprising cabazitaxel and cisplatin, cabazitaxel being in the form of a free base or of an addition salt with a pharmaceutically acceptable acid, or in the form of a hydrate or a solvate; and a label or package insert contained within said packaging material indicating that said pharmaceutical combination is administered to the patient in a recommended dose (RD) or a maximum tolerated dose (MTD), and in a plurality of subsequent doses in a recommended dose (RD) or a maximum tolerated dose (MTD), separated from each other in time by three weeks. The combination is administered repeatedly over the course of several cycles according to a protocol that depends on the nature and stage of the cancer to be treated and also on the patient to be treated (age, weight, previous treatment or treatments, etc. ).

Examples of cycles and doses are given in Example 2 below.

Example 1:

The improved efficacy of the combination according to the invention can be demonstrated by determining the therapeutic synergy as illustrated in the following example.

In this example, the efficacy of a cabazitaxel / cisplatin combination of the invention in inhibiting tumor growth was demonstrated in vivo.

The selected tumor model was a murine tumor, C51 colon adenocarcinoma, grafted onto the syngeneic strain of mice of tumor origin, BALB / C mice [TH Corbett et al., Cancer, 40: 2660-2680 (1977)].

Cabazitaxel was weighed for each treatment and dissolved in ethanol. Treatment solutions were first prepared by mixing 1 volume of ethanolic stock solution and 1 volume of polysorbate 80, then adding 18 volumes of 5% glucose in water.

Cabazitaxel was administered intravenously on days 5, 12 (or 13) after tumor implantation. Cisplatin was formulated in 0.9% NaCl, pH 4.5. Cisplatin was administered intravenously on days 5, 12 (or 13) after tumor implantation, with an interval of 15 min or 24 h with cabazitaxel.

The results of the experiment are presented in Table 1.

The tumor doubling time was 2.5 days.

The following endpoints have been used:

- Toxicity was declared in dosages that induced> 20% loss of body weight or> 10% death from the drug.

Inhibition of tumor growth was determined on day 20 after tumor implantation when the median tumor size in the control group was 1352 mg.

Tumors in the treatment (T) and control (C) groups were measured when the median of the control group reached approximately 750 to 1400 mg. The median tumor weight of each group was determined.

- The antitumor efficacy was determined by calculating the T / C value in percentage:

T / C (%) = Median tumor weight of the treated / control group x 100

According to NCI standards, a T / C <42% is the minimum level to declare activity. A T / C <10% is considered to indicate high antitumor activity and is the level used by NCI to warrant further development (decision network level 2, DN-2).

- To better quantify antitumor activity, another endpoint was used, the cell destruction log:

log 10 cell destruction = (T-C) / [3.32 x (tumor doubling time in days)]

(T denoting the median time of the treated mice to reach 750 mg and C the median time (17.6 days) of the control mice to reach the same size). No antitumor activity was declared for log destruction cell <0.7, and the treatment was declared very active for log destruction cell> 2.8

- Therapeutic Synergy: a combination has therapeutic synergy if it is more active than the best individual agent in the study (in at least 1 log cell destruction).

Cabazitaxel toxicity was only observed at a dose of 32.3 mg / kg / injection, resulting in 6/6 drug-related deaths from day 19 to day 24. The highest non-toxic dose (HNTD) was found for cabazitaxel, 20 mg / kg / iny (total injected dose = 40 mg / kg), was active with a cell destruction log of 1.8. The lowest doses of 12.4 and 7.7 mg / kg / iny remained active with a cellular destruction log of 1.4 and 1.3, respectively.

Cisplatin toxicity was only observed at a dose of 7 mg / kg / injection, with 2/6 drug-related deaths occurring on days 8 and 23, and a loss of 24.6% body weight was observed in the nadir of the day 17, that is, approximately the 20% threshold. The HNTD for cisplatin, 4.3 mg / kg / iny (total injected dose = 8.6 mg / kg), was found to be active with a cell kill log of 2.7. The lowest dose 2.7 mg / kg / iny remained active with a cell destruction log of 1.8.

Using a 15 min interval between administrations of the 2 agents, the combination of cisplatin at 3.5 mg / kg / iny with cabazitaxel at 10 mg / kg / iny was declared toxic, with 19.5% loss of body weight at the nadir of day 20. The dose of 2.8 mg / kg / iny of cisplatin combined with 8 mg / kg / iny of cabazitaxel was considered to be HNTD. Remarkably, this dose was found to be very active with a cell destruction log of 4.6, clearly much more active than the activity of each agent administered alone. Likewise, greater antitumor activity was also observed at the dose below HNTD (2.1 mg / kg / iny of cisplatin with 6 mg / kg / iny of cabazitaxel) with a log cell destruction of 3.6.

It can thus be concluded that this combination shows a therapeutic synergy.

Using a 24 h interval between the administrations of the 2 agents, two different orders of administrations have been evaluated, cabazitaxel first on days 5 and 12, with cisplatin being administered 24 h later on days 6 and 13, or the reverse sequence being administered cisplatin first.

- Cabazitaxel first: The combination of cabazitaxel at 13 mg / kg / iny with cisplatin at 4.6 mg / kg / iny was declared toxic, with 1/6 drug-related deaths, and 27.5% weight loss Body dose at day 21 nadir. The dose of cabazitaxel at 10 mg / kg / iny followed 24 hours later by cisplatin at 3.5 mg / kg / iny was considered to be HNTD. This dose was found to be very active with a cell destruction log of 4.6, being clearly much more active than the activity of each agent administered alone, as previously observed in combination with the 15 min interval. Interestingly, increased antitumor activity was also observed at 2 doses below the HNTD (combination of cabazitaxel / cisplatin at 8 / 2.8 and 6 / 2.1 mg / kg / iny), with a cell destruction log of 4.1 and 3.7, respectively.

It can thus be concluded that using this administration sequence with an interval of 24 h with cabazitaxel being injected first, this combination also shows a therapeutic synergy.

- Cisplatin first: The combination of cisplatin at 4.6 mg / kg / iny with cabazitaxel at 13 mg / kg / iny was declared toxic, with 20.6% loss of body weight at day 19 nadir. he considered that the dose of cisplatin at 3.5 mg / kg / iny followed 24 h later by cabazitaxel at 10 mg / kg / iny was HNTD. As previously observed when cabazitaxel was first administered, this HNTD was highly active with a cell destruction log of 4.4. Greater antitumor activity was also observed at 2 doses below HNTD (combination of cisplatin / cabazitaxel at 2.8 / 8 and 2.1 / 6 mg / kg / iny), with a log cell destruction of 4.1 and 3.5, respectively.

It can thus be concluded that using this administration sequence with an interval of 24 h with the cisplatin being injected first, this combination also shows a therapeutic synergy.

In conclusion, the combination of cabazitaxel-cisplatin shows therapeutic synergy as long as the sequence of administration of the agents (a: log cell destruction of 4.4 to 4.6 for the combination versus log cell destruction of 1.8 for the cabazitaxel alone and log cell destruction of 2.7 for cisplatin alone). In addition, this therapeutic synergy was maintained at dosages below HNTD at dose levels one (15 min separation) and 2 (24 h separation).

Example 2:

This example describes a clinical study evaluating the safety, tolerability, pharmacokinetics, and efficacy of a cabazitaxel / cisplatin combination of the invention administered every 3 weeks in patients with advanced solid cancer.

TITLE

A dose-escalation study of the safety, tolerability, and pharmacokinetics of cabazitaxel in combination with cisplatin given every 3 weeks in subjects with advanced solid malignancies OBJECTIVE (S) OF STUDY

Primary Objectives:

• Part 1:

To determine the dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of cabazitaxel administered as a 1-hour infusion in combination with cisplatin every 3 weeks in patients (pts) with advanced solid malignancies.

• Part 2:

To determine the anti-tumor activity of cabazitaxel in combination with cisplatin, as assessed by the degree of response sought (ORR) according to the RECIST criteria.

Secondary Objectives:

- Assess the safety profile of the combination regimen of cabazitaxel with cisplatin.

- Evaluate the pharmacokinetics (PK) of cabazitaxel and cisplatin, and evaluate any PK drug-drug interaction between the compounds following this administration scheme.

- Determine the time to progression (TTP) and duration of response (DR) of the prolonged cohort of sts treated for BAT in Part 2 of the study and patients receiving BAT in the component of Part 1. DESIGN OF THE STUDY

The study is designed in Parts 1 and 2 as an open-label, single-branch, multicenter, dose-escalation study of cabazitaxel in combination with cisplatin, to determine:

Part 1: DLTs and BAT based on security,

Part 2: the antitumor activity of the combination regimen to BAT in a prolonged pts cohort,

In Part 1, as shown in the table below, the 3-6 pt cohorts were treated with cabazitaxel and cisplatin on Day 1 every 3 weeks. The starting dose (Dose level 0) will be 20 mg / m2 for cabazitaxel and 75 mg / m2 for cisplatin every three weeks.

Dose Scaling Scheme:

For safety reasons, the actual dose of cabazitaxel will be adjusted up to a maximum BSA of 2.1 m ²

The dose escalation criteria described in the table below must be met at each dose level during cycle 1 in order to include and treat pts at the next dose level.

Cabazitaxel dose escalation decision rules:

At each given dose level, there will be a gap of one week to assess toxicity, between the inclusion of the first pt and the following 2 pts. Before escalation to the next dose level, at least 3 pts would be evaluable for the criteria that define a DLT.

Limiting Dose Toxicities (DLT) and Maximum Tolerated Dose (BAT):

To qualify for DLT, the clinical adverse event (AE) or laboratory abnormality must be drug related as assessed by the investigator or sponsor.

DLTs will be defined (according to the NCI-CTCAE version 3 graduation scale) during the first treatment cycle, as follows:

• Non-hematological toxicity grade 3 or 4, except:

- Grade 3 fever without documented infection

- Grade 3 nausea, vomiting, or diarrhea in the absence of maximum effective therapy

- Grade 3 mucositis / stomatitis in the absence of effective symptomatic treatment

- Grade 3 fatigue

- Grade 3 anorexia

- Grade 3 elevation of AST / ALT (aspartate aminotransferase / alanine aminotransferase) that returns to the reference value before the next treatment cycle

- Grade 3 HSR (acute hypersensitivity reaction) in the absence of required premedication

- Grade 3 peripheral neuropathy that returns to grade 1 or less at the beginning of the next treatment cycle

- Any other life-threatening drug-related clinical toxicity

• Hematological toxicity defined as:

- Febrile neutropenia: fever (of unknown origin without clinically or microbiologically documented infection)> 38.5 ° C with grade 3 or 4 neutropenia

- Neutropenia grade 4 lasting> 7 days

- Platelets / thrombocytopenia grade 4

In the case of the presence of a DLT in the first cycle, 3 additional pts will be included in the same dose level and the MAD (maximum administered dose) will be reached at the dose level when at least 2 pts develop a DLT in the first cycle.

The prophylactic and therapeutic use of hematopoietic growth factors is not allowed during the first 3 weeks of study treatment unless a hematologic DLT is found.

Maximum Tolerated Dose (BAT):

BAT will be defined as the highest dose at which 0 or 1 of 3 or 6 pts, respectively, experience DLT during the first 3 weeks of combination of cabazitaxel and cisplatin. If there is a dose decrease to Cabazitaxel Dose Level -1, BAT will be established at this dose level.

Once the BAT of cabazitaxel in combination with cisplatin has been established, the safety, PK and preliminary efficacy of this regimen will be evaluated in an additional 15 patients in the Part 2 component of the study. Patients will be closely monitored for toxicity. In addition to optimizing supportive care, chemotherapy doses can be adjusted after the first cycle of therapy and recovery to grade <1 or the reference value. Dose escalation between patients is not allowed. For patients who have had DLT, further treatment at a lower dose is at the discretion of the investigator.

No additional cycles will be evaluated for MAD or BAT. However, safety and efficacy data continue to be collected.

All patients treated in Parts 1 and 2 will continue to receive treatment until disease progression, unacceptable toxicities / adverse events, withdrawal of consent, or withdrawal decision by the investigator, whichever comes first.

STUDY POPULATION

Inclusion criteria:

- Age> 18 years

- Histologically or cytologically confirmed advanced solid malignancy that is metastatic or untreatable, and for which there are no standard curative measures, but for which cisplatin-based therapy is appropriate

- Eastern Cooperative Oncology Group (ECOG) Behavioral Status (PS) <1

- Presence of measurable disease (part 2 only)

- No treatment with cisplatin 6 months before the start of the study

- No cancer therapy 3 weeks before the start of the study

- No simultaneous treatment in another clinical trial or with any other cancer therapy

- No continued toxic effects from previous cancer therapy

- Adequate white blood cells, platelets, hemoglobin, and liver and kidney function.

Exclusion criteria

- inability to follow the requirements and outline of the study

- cancer treatment 3 weeks before the study, simultaneous treatment in another clinical trial or with other cancer therapy

- serious illness at the same time of the study and / or significantly abnormal laboratory reports

- absence of contraception (potentially fertile women), pregnancy or lactation.

- previous significant hearing or kidney problems

- continued toxic effects of previous chemotherapy

- cancers that cannot be physically measured (Part 2 only)

- Inadequate organic function as defined by: Absolute Neutrophil Count (ANC) <1500 / mm3; Platelets <75,000 / mm, Hemoglobin <9.0 g / dl; Prothrombin time / International normalized ratio (PT / INR)> 1.5; Estimated creatinine clearance (CrCI) <60 ml / min, or serum creatinine> 1.0 x ULN;

RESEARCH PRODUCT OR PRODUCTS

Cabazitaxel

Cabazitaxel is supplied as a sterile, non-pyrogenic, non-aqueous, yellowish to brownish yellow 60 mg / 1.5 ml concentrate for solution for infusion. It is packaged in a clear 15 ml single-dose type I glass vial. The solution contains the following excipient: polysorbate 80. Solvent: The solvent for cabazitaxel is supplied as a solution in 13% m / m ethanol in water for injection. This solvent is supplied in a clear 15 ml single-dose Type I glass vial. Preparation of the cabazitaxel infusion solution for administration first requires the preparation of a premix solution at 60 mg / 6 ml (10 mg / ml) (nominal concentration). Each cabazitaxel vial should be diluted with the entire contents of one vial of solvent. Each cabazitaxel vial and each solvent vial are overloaded to ensure that a 60 mg dose can be withdrawn after preparation of the premix solution. The premix solution must then be diluted in an infusion vehicle (0.9% NaCl or 5% glucose) to obtain the dose required for administration.

Cisplatin:

75 mg / m2 of cisplatin in 500 ml of 0.9% NaCl will be administered IV over 1 hour on Day 1, 1 hour before cabazitaxel administration. Commercially available cisplatin will be used to prepare the IV infusion. Appropriate pre and post supportive medications that provide hydration, an antiemetic, and dexamethasone will be administered.

Route or routes of administration:

Cabazitaxel and cisplatin: intravenous.

Dosage regimen:

Part 1:

Cisplatin will be administered first followed by infusion of cabazitaxel. Both infusions must be administered through different infusion lines.

a) On day 1 of each cycle, infusion of cisplatin at 75 mg / m2 in 500 ml of 0.9% NaCI IV will be administered over 1 hour.

b) On day 1 of each cycle, patients will receive cabazitaxel, administered by IV infusion over 1 hour, in the dose specified for each level. IV premedications including antihistamines would be administered by infusion 30 minutes before cabazitaxel administration.

For patients who have had DLT, further treatment at a lower dose is at the discretion of the investigator. Additional cycles will not be evaluable with respect to MAD or MTD. However, safety and efficacy data will continue to be collected.

Part 2:

Patients will receive both cabazitaxel and cisplatin on day 1 of each cycle in the same manner as in Part 1. Cycle lengths in both Part 1 and Part 2, for this treatment combination, are 3 weeks.

Parts 1 and 2:

New therapy cycles cannot begin until ANC (absolute neutrophil count) tests> 1500 / mm3, platelet count> 75,000 / mm3, serum creatinine <1.5, blood urea nitrogen <25 mg / dl, liver function is within a range as indicated in the exclusion criteria, and non-hematologic toxicities (except alopecia, asthenia, local reactions, and other toxicities that are unpleasant but do not cause severe morbidity in patients) have recovered to a degree <1 or the reference value.

A dose modification may be required as detailed in the protocol. A maximum of 2 weeks of treatment delay is left between treatment cycles. Patients should discontinue study treatment if the treatment delay is greater than 2 weeks.

PRIMARY CRITERIA OR VALUATION CRITERIA AND MAIN SECONDARY CRITERIA OR VALUATION CRITERIA

The primary endpoint of the study will be:

Part 1: DLTs in cycle 1 of the combination of cabazitaxel and cisplatin.

Part 2: Anti-tumor activity based on RECIST criteria, including BAT patients who have continued since Part 1.

Efficacy will be determined using the sought responses (CR, ie full response and PR, ie partial response) as assessed by the investigators according to the RECIST criteria. Confirmation of the sought responses will be performed by repeat tumor imaging (CT (digital tomography), MRI (magnetic resonance imaging)) scans 4-6 weeks after the first radiological response documentation.

Evaluations of the primary secondary endpoints will include:

1. TTP (parts 1 and 2)

2. DR (parts 1 and 2)

3. Combination safety profile regarding AEs / SAEs and laboratory parameters

4. PK of cabazitaxel (parts 1 and 2) and cisplatin (part 1)

ASSESSMENT SCHEME

Security data:

Vital signs, medical history, physical exams, ECOG PS, EKG, and laboratory safety tests (including complete blood counts, serum chemistry, and urinalysis) will be obtained prior to drug administration at designed intervals. through study. Adverse events from treatment (TEAEs) will be collected during the study and up to 30 days after the end of study treatment. Any SAEs considered related to study medication will be collected regardless of when they occur. AEs will graduate according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 (NCI CTCAE v.3.0).

Efficacy Data:

In parts 1 and 2, anti-tumor activity will be assessed by digital tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen, pelvis and / or other areas of tumor burden. These examinations will be carried out in the reference situation (screening), at the end of each even number treatment cycle (that is, days 15-21 of cycles 2, 4, 6, ...), whenever progression is suspected. of the disease and at the end of the treatment / withdrawal visit, using the same method for each assessment. For bone, the examination will be performed in the reference situation and whenever new or worsening bone symptoms occur, and at the time an evaluation of the tumor is performed to confirm a response.

Patients who discontinue study treatment prior to disease progression will continue to have tumor evaluations every 6 weeks until disease progression or the start of other anticancer therapy.

PK data:

Part 1: Cabazitaxel PK - Blood samples (2 ml each) will be collected for PK analysis from all patients in Cycle 1 as detailed in the protocol. Cisplatin PK - Blood samples (5 ml each) will be collected for PK analysis from all patients in Cycle 1 for quantification of plasma-bound and free platinum derivative with an appropriate duration as detailed in the protocol.

Part 2: Cabazitaxel PK - Blood samples (2 ml each) will be collected for PK analysis from all patients in cycle 1 and cycle 2 as detailed in the protocol

STATISTICAL CONSIDERATIONS

Part 1:

Approximately 15 patients will be required to establish the MTD and tolerability of the combination with a planned number of 3 dose levels (3 to 6 patients per dose level). Analysis population: Treated population defined as all patients taking at least part of a dose of cabazitaxel or cisplatin. Statistical analysis will be descriptive. The variables of the analyzes are:

• DLT as the primary analysis variable,

• TEAE, Laboratory.

The deadline for Part 1 Safety Review: End of Cycle 1 received by the last patient listed in this Part.

Part 2:

Approximately 15 additional patients have accumulated in addition to patients receiving BAT in the Part 1 component.

Analysis populations:

• Treated population: all patients taking at least part of a dose of the study medication cabazitaxel.

• Population per protocol: treated patients who met the following requirements: a) with 2 minimum cycles of treatment or early withdrawal due to toxicity, progression or death within the same period; b) They have a valid reference value and at least one evaluation of the tumor after the reference situation.

The variables of the analyzes are:

Effectiveness:

• Global response sought (PR or CR) as the primary endpoint,

• TTP

• DR

• Security:

• TEAE, SAEs, Laboratory.

Statistical Methods:

An exact 95% confidence interval will be provided for the sought response speed for the treated population and per protocol. Kaplan-Meier curves and mortality tables will be provided for the TTP treated population and the duration of response (DR) among patients who have partial or complete responses.

The deadline for Part 2: when the last patient has completed 6 cycles of treatment or discontinued study treatment (due to disease progression, unacceptable toxicity, withdrawal of consent, or withdrawal decision by the investigator), whichever occurs first.

DURATION OF THE STUDY PERIOD (per subject)

The study consists of

• A maximum of 21 days from the screening phase,

• Registry,

• Study drug administration begins 5 business days after registration, with study treatment cycles of 21 days. Cycle lengths can be extended up to a maximum of 2 additional weeks in case of unresolved toxicity.

• All treated patients will continue to receive treatment until disease progression, unacceptable toxicity, withdrawal of consent or decision of withdrawal by the investigator, whichever occurs first.

• There will be a 30-day follow-up visit after the last dose of study medication. In Parts 1 and 2, patients who discontinue study treatment prior to disease progression will continue to have tumor evaluations every 6 weeks until disease progression or the start of other anticancer therapy.

• Deadline for parts 1 and 2: when the last patient has completed 6 treatment cycles or interrupted study treatment (due to disease progression, unacceptable toxicity, withdrawal of consent or decision to withdraw by the researcher), what that occurs first, in the corresponding part. Patients still receiving treatment by the due date may continue to receive treatment beyond the due date at the investigator's discretion if they benefit.

RESULTS

• A total of 25 patients were enrolled and treated in the study (Part 1 Part 2) at 2 dose levels (DL). Ten (10) patients were treated during the dose escalation phase (Part 1): 7 patients at DL 20/75 and 3 patients at DL 15/75. Fifteen (15) patients were incorporated and treated in Part 2 to the BAT determined in Part 1 (DL 15/75). In total, 18 patients were treated for BAT in the study.

• Disease progression was the most frequent reason for discontinuation of treatment in general (12/25 patients, 48.0%) and in patients treated for BAT (10/18 patients, 55.6%). A total of 9 patients (9/25 patients, 36.0%) discontinued study treatment due to an adverse episode (AE). This included 4 patients (4/18 patients, 22.0%) treated with BAT.

• The demographics and reference characteristics of the population treated for BAT are as follows. The median age was 56.5 [32-71] years. ECOG status was 0 or 1. Patients with a wide variety of cancers were included (no more than 2 patients had the same type of tumor); lung, pancreas and prostate cancer were each presented by 2 patients; all other types of cancer were each presented by a patient. The median number of organs involved was 3.0 [1-6]. The main organs involved (> 20%) were the lymph nodes, the lungs and the liver. Previous anticancer therapies were surgery in 55.6%, radiotherapy in 66.7% and previous chemotherapy in 100% of the patients. The most common laboratory abnormalities (all grades) at baseline were anemia (77.8%) and lymphopenia (50.0%) for hematology and increased alkaline phosphatase (50.0%), hypercholesterolemia (33 , 3%) and an increase in ASAT (27.8%) for biochemistry.

SECURITY

• Two (2) of 6 evaluable patients experienced DLT at dose level 0 (DL 20/75): 1 acute renal failure grade 3 and 1 febrile neutropenia. None of the 3 patients treated at a dose level of -1 (DL 15/75) experienced DLT. DL 15/75 was defined as the BAT for Part 2.

• At BAT, 60 cycles were administered to 18 patients. The median number of cycles per patient was 3 [1-8]. Three (3) patients received more than 6 cycles of study treatment: 2 patients received 7 cycles and 1 patient received 8 cycles. The median relative dose intensity (RDI) was 0.95 [0.74-1.02] for cabazitaxel and 0.98 [0.71-1.01] for cisplatin. Five (5) of 15 patients (33.3%) had at least 1 dose reduction for either cabazitaxel or cisplatin, with 1/15 patients (6.7%) having at least 1 dose reduction for cabazitaxel and 4/15 patients (26.7%) with at least 1 dose reduction for cisplatin. The most frequent TEAE (in at least 2 patients) leading to a dose reduction was an increase in blood creatinine (in 2 patients). • At BAT, the 5 most common TEAEs of all grades were nausea (77.8%), vomiting (72.2%), decreased appetite (66.7%), fatigue (61.1%), diarrhea and anemia (44.4% each). Grade 3-4 TEAEs occurred in 77.8% of patients. The most frequent (in more than 2 patients) were nausea, anemia (each in 22.2% of patients), fatigue, and decreased neutrophil count (each in 16.7% of patients).

• TEAEs in System Organ Class renal and urinary disorders were present in 3/18 (16.7%) patients at BAT (all grades and grade> 3). Two (2) patients experienced grade 3 acute renal failure and 1 patient experienced grade 3 renal tubular necrosis.

• A total of 9 patients discontinued study treatment due to AE or ESA. This included 4 MTD patients who discontinued treatment due to increased blood creatinine (2 patients), increased blood urea (1 patient), and drug hypersensitivity (1 patient).

• Nine (9) patients died due to disease progression. Two (2) patients experienced TEAE or lethal TEAEs: 1 patient in group DL 20/75 experienced grade 4 septic shock (considered possibly related to study treatment) and died within 30 days from the last administration of study treatment and 1 MTD patient experienced a grade 4 disease progression EA and died during the follow-up period. One patient died during the follow-up period from an unknown cause.

• Overall, 16/25 patients (64.0%) experienced severe TEAEs (all grades). At BAT, 11/18 patients (61.1%) experienced severe TEAEs (all grades and grade>3); the most frequent severe ASDs (all grades and grades> 3) were nausea, vomiting, neutropenia, acute kidney failure, and decreased appetite, each occurring in 2/18 patients. The other severe ASDs occurred in individual patients.

• Neutropenia was the most common grade> 3 hematologic abnormality (based on laboratory values) overall (21/25 patients, 84.0%) and BAT (14/18 patients, 77.8%).

EFFECTIVENESS

• At BAT, there was no CR or PR in the populations per protocol (n = 15) and "of all treated" (n = 18) (Part 1 and Part 2).

• Eleven (11) patients in the “all treated” population had DS. These patients had the following primary tumor areas: pancreas (2 patients), prostate (2 patients), lungs (2 patients), pleura, endometrium, esophagus, ovaries, and ependymoma. Among these patients, 1 patient with prostate adenocarcinoma had unconfirmed RP in Cycle 6 and progressed in Cycle 8.

PHARMACOKINETICS

• Exposure to cabazitaxel (AUC) during Cycle 1 increased proportionally to the dose between 15 and 20 mg / m2 of cabazitaxel when administered in combination with cisplatin: a 1.33-fold increase in dose gave resulted in a 1.25-fold increase in AUC.

• The PK of cabazitaxel did not appear to be changed by cisplatin infusion.

• The PK of cisplatin (total and free) in this study (cisplatin dose: 75 mg / m2) was similar to that previously reported (AUCfinal = 45,820 ng.h / m for total platinum and AUCfinal = 4170 ng.h / ml for free platinum), indicating that cabazitaxel did not appear to alter the PK of cisplatin following this schedule of administration.

CONCLUSION

• The MTD for cabazitaxel is 15 mg / m2 on Day 1 when combined with cisplatin at the 75 mg / m2 dose on Day 1, administered every 3 weeks.

• DLTs submitted to MAD (impaired renal function and febrile neutropenia) were expected and were consistent with a taxane combined with platinum.

• Part 2 of the study confirmed BAT, with 15 patients treated and 2 patients with DLT in Cycle 1 (1 febrile neutropenia and 1 grade 3 hypersensitivity reaction despite appropriate premedication). The overall safety profile was expected for a taxane combined with platinum and was manageable.

• Cabazitaxel PK did not appear to be altered by cisplatin infusion. Cabazitaxel did not appear to alter the PK of cisplatin (total and free).

Claims (12)

1. Combination comprising cabazitaxel, which may be in the form of an anhydrous base, a hydrate or a solvate, and cisplatin, said combination being for administration of cabazitaxel by infusion at a dose of 15 to 25 mg / m2 and for the administration of Cisplatin by infusion at a dose of 75 mg / m2, for use in the treatment of cancer. 2. Combination for use according to claim 1, wherein the cabazitaxel is in the form of a solvate. 3. Combination for use according to claim 2, wherein the solvate is an acetonic solvate. 4. Combination for use according to claim 3, wherein the acetone solvate contains between 5% and 8% by weight of acetone. 5. Combination for use according to claim 1, for administration of cabazitaxel by infusion at a dose of 15 mg / m2 and for administration of cisplatin by infusion at a dose of 75 mg / m2. 6. Combination for use according to claim 1, wherein the cycle of administration of the two antitumor agents is repeated with an interval between two administrations of cabazitaxel of three weeks. 7. Combination for use according to claim 1, wherein cabazitaxel and cisplatin are administered simultaneously, semi-simultaneously, separately or spaced over a period of time. 8. Combination for use according to claim 1, wherein the amount of cabazitaxel represents 10 to 90% by weight of the combination. 9. Combination for use according to claim 1, wherein cabazitaxel and cisplatin are both administered parenterally. 10. Combination for use according to claim 9, wherein cabazitaxel and cisplatin are both administered intravenously. 11. A pharmaceutical kit, comprising: (i) a first galenic formulation comprising cabazitaxel in the form of a free base or an addition salt with a pharmaceutically acceptable acid, or in the form of a hydrate or a solvate; (ii) a second galenic formulation comprising cisplatin; for administration of cabazitaxel by infusion at a dose of 15 mg / m2 and for administration of cisplatin by infusion at a dose of 75 mg / m2. Both galenic formulations (i) and (ii) are intended to be administered independently, each administration with respect to the other being simultaneous, separated or extended in time for use in the treatment of cancer. 12. A pharmaceutical kit for use according to claim 11, wherein the cycle of administration of the two antitumor agents is repeated with an interval between two administrations of cabazitaxel of three weeks.